Targeting the Mitochondrial Permeability Transition Pore: A Translational Approach to Prevent Myocardial Reperfusion Injury in Delayed Percutaneous Coronary Intervention

Timely revascularization is the cornerstone of limiting ischemic cell death in acute myocardial infarction (MI) (1). However, delayed percutaneous coronary intervention (PCI) paradoxically poses a significant threat to the myocardium, leading to lethal reperfusion injury—a major clinical problem contributing to adverse outcomes despite successful epicardial reperfusion (2). Microvascular injury resulting from delayed reperfusion, first documented in the 1960s, significantly exacerbates myocardial injury (3). The pathogenesis of lethal reperfusion injury is driven by three central paradoxes: the calcium paradox, involving a pathological surge in intracellular calcium; the oxygen paradox, characterized by a burst of reactive oxygen species (ROS); and the pH paradox, marked by the rapid normalization of intracellular pH (4). These converge to induce mitochondrial permeability transition pore (MPTP) opening, resulting in mitochondrial damage and cardiomyocyte death (5). Despite elucidation of these mechanisms in experimental models, translation to clinical cardioprotection has been challenging (6). This review explores the mechanistic pathways of reperfusion injury, discusses the failures and promises of therapeutic strategies, and highlights future translational directions for protecting the myocardium in the context of delayed PCI. Therefore, overcoming translational challenges by developing targeted combination therapies and refining patient selection based on individual pathophysiology is the crucial next step to harness the therapeutic potential of MPTP inhibition and significantly improve outcomes in delayed PCI (7).